Double‐Blind, Placebo‐Controlled, Lamotrigine in Treatment‐Resistant Generalised Epilepsy

Beran, Roy G.; Berkovic, Samuel F.; Dunagan, F. M.; Vajda, Frank J. E.; Danta, G; Black, Andrew; MacKenzie, Ross

doi:10.1111/j.1528-1157.1998.tb01332.x

Cited by 105 publications

(71 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lamotrigine (LTG), like PHT and CBZ, blocks Na" channels (59); but, unlike them, LTG has a beneficial effect in some forms of IGE (60,61). This pharmacodynamic difference may be due to the multiplicity of mechanisms of action of LTG, including but not limited to, inhibition of Ca2+ currents (62,63) that drive the pathological thalamocortical rhythms of AE (64).…”

Section: Discussionmentioning

confidence: 99%

Refractory Idiopathic Absence Status Epilepticus: A Probable Paradoxical Effect of Phenytoin and Carbamazepine

2000

View full text Add to dashboard Cite

Summary: Purpose:To compare the frequency of seizures and status epilepticus and their response to first-line drugs in patients with idiopathic generalized epilepsies receiving carbamazepine or phenytoin to those receiving other drugs or no treatment.Methods: We performed a retrospective chart review of all cases of idiopathic generalized epilepsies treated by the authors between 1985 and 1994. We compared seizure frequency and mean intravenous benzodiazepine dose required to control absence status epilepticus, intraindividually in subjects on carbamazepine or phenytoin before and after discontinuation of these compounds, and interindividually to subjects without treatment or receiving other drugs.Results: Bouts of absence or tonic-clonic status epilepticus and seizures in subjects treated with phenytoin or carbamazepine at therapeutic concentrations were considerably more frequent and proved intractable to treatment with valproic acid or benzodiazepines, compared with a cohort of subjects also with idiopathic generalized epilepsies, but naive to, or receiving subtherapeutic or therapeutic doses of other agents.Conclusions: Our observations strongly suggest that therapeutic concentrations of phenytoin and carbamazepine exacerbate idiopathic generalized epilepsies. Subjects in whom absence is one of the seizure types seem at a particularly high risk for responding paradoxically. These findings underscore the value of accurate classification of seizures and particularly the syndromic approach to diagnosis and point to the potential for iatrogenic complications with indiscriminate use of antiseizure drugs. Key Words: Idiopathic generalized epilepsiesAbsence status epilepticus-Refractoriness-Paradoxical effects-Phenytoin-Carbamazepine.Convulsive status epilepticus refractory to appropriate treatment is well recognized and comprises a sizable percentage of all cases of status (1,2). In contrast, idiopathic generalized absence status epilepticus (IGASE), refractory to appropriate drugs, is rate (3-6). A survey of the literature revealed that complete control was attained in 93% of cases from 10 different studies (7).Paradoxical increases in seizure frequency is a recognized, but difficult-to-document, adverse effect of antiepileptic agents (8-10). The main limitation evident in the existing body of literature is a lack of systematic observations over reasonably long periods of time to minimize the confounding effect of the inherently high variability in seizure frequency, a phenomenon known as "regression of seizure frequency to the median" (9, I 1 ).In addition, the majority of reported cases have been patients with symptomatic epilepsy. We report eight carefully studied cases (Group 1) with idiopathic generalized epilepsy (ICE) on phenytoin (PHT) and carbamazepine (CBZ) with very frequent, seemingly intractable absence (AS) and tonic-clonic seizures who presented in absence status epilepticus (ASE) that proved refractory to intravenous high-dose benzodiazepines (BZDs). The lack of response in these cases was in star...

show abstract

Section: Discussionmentioning

confidence: 99%

Refractory Idiopathic Absence Status Epilepticus: A Probable Paradoxical Effect of Phenytoin and Carbamazepine

2000

View full text Add to dashboard Cite

show abstract

“…LTG is a weak folate antagonist and possesses a spectrum of activity in animal seizure models similar to those of PHT and CBZ (108). However, unlike these traditional agents, LTG appears to have efficacy against generalized epilepsies (109). Although structurally unrelated to PHT and CBZ, LTG has been demonstrated to block sodium channels in a voltage-, use-, and frequency-dependent manner, preventing propagation of action potentials and the release of neurotransmitters, principally glutamate (7).…”

Section: Lamotriginementioning

confidence: 99%

The Pharmacologic Basis of Antiepileptic Drug Action

1999

View full text Add to dashboard Cite

Summary:The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, neTherapy with antiepileptic drugs (AEDs) remains the mainstay of treatment of patients with epilepsy. Before the Victorian era, therapeutic approaches to epilepsy were largely based on superstition and charlatanism. The first demonstrably effective chemotherapy relied on the use of nonspecific depressants of the central nervous system. Sir Charles Locock introduced bromides in the mid-nineteenth century for the treatment of catamenial epilepsies, and phenobarbital (PB) was adopted in 1912 after the observations of Hauptmann (l), who used that compound to sedate a ward of noisy psychiatric patients and those with epilepsy during the night. Introduction of more specific AEDs for clinical application followed the availability of the first animal-seizure model: the maximal electroshock (MES) model (2). The history of AED design has recently been reviewed in some detail (3).The relation of the human epilepsies to the animal models commonly used for AED development, and to the cellular membrane physiology underlying neuronal excitability, continues to be an imperfect one (Fig. 1) cessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action. Key Words: Antiepileptic drug-AED-Anticonvulsant-Mechanism-%-zure-Epilepsy-Ion channel.threshold pentylenetetrazol (PTZ) test in mice (see Table 1) have been carefully standardized (4). The MES model has served to identify AEDs that are functionally similar to phenytoin (PHT), and most of these compounds display in common the ability to inactivate voltage-dependent Na+ channels in a use-dependent fashion. Such compounds suppress sustained repetitive firing in cultured neurons. Activity in this model seems highly predictive of the ability of those AEDs to protect against partial and secondarily generalized tonic-clonic seizures (Fig. 2). Carbamazepine (CBZ), as well as several newer agents such as felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), and topiramate (TPM), fit this model of AED activity. Some of these (i.e., PHT, CBZ, LTG) may also attenuate the release of excitatory neurotransmi...

show abstract

“…In a multicenter, double-blind, placebo-controlled crossover study, 26 patients with refractory generalized epilepsy were treated with LTG for 8 weeks (22). LTG doses were 75 mglday when VPA was concurrent and 150 mglday when enzyme-inducing drugs were in use.…”

Section: Generalized Epilepsymentioning

confidence: 99%

Lamotrigine

Matsuo

1999

Epilepsia

View full text Add to dashboard Cite

Summary: Clinical use of the antiepileptic drug (AED) lamotrigine (LTG) has dramatically increased since its introduction in Europe in 1991 and in the United States in 1994. This article surveys the English-language literature of LTG published before 1998. This literature is concerned with the molecular mechanisms of LTG's antiepileptic action, evaluation of its clinical antiepileptic efficacy, adverse experiences associated with its clinical use, and current guidelines for its initiation. LTG's efficacy has been extensively confirmed in multiple postmarketing studies, and its applications are broad. The most serious adverse experiences have involved skin rash. Valproic acid affects LTG metabolism, and a specific set of guidelines for the concurrent use of valproic acid and LTG has been developed. Unique issues are also associated with its pediatric use. LTG has a significant place in clinical management of a wide range of epilepsy syndromes, and the scope of its use is expanding. Accumulating clinical data enable the clinician to maximize its efficacy and minimize adverse experiences. Guidelines for its pediatric use must be followed diligently.

show abstract

Double‐Blind, Placebo‐Controlled, Lamotrigine in Treatment‐Resistant Generalised Epilepsy

Cited by 105 publications

References 20 publications

Refractory Idiopathic Absence Status Epilepticus: A Probable Paradoxical Effect of Phenytoin and Carbamazepine

Refractory Idiopathic Absence Status Epilepticus: A Probable Paradoxical Effect of Phenytoin and Carbamazepine

The Pharmacologic Basis of Antiepileptic Drug Action

Lamotrigine

Contact Info

Product

Resources

About